The present invention, in some embodiments thereof, relates to pharmaceutical and/or cosmetic compositions, and more particularly, but not exclusively, to stabilize compositions for neutralizing malodor in mucous membranes and occluded skin areas.
Mucous membranes secrete an aqueous fluid rich in glycoproteins that normally has no offensive odor. For example, normal vaginal discharge may change consistency and color during the menstrual cycle but typically is it is not characterized by malodor. Nonetheless, unpleasant malodor in the genital area and around it is quite common in women, and other than being a source of embarrassment. It is oftentimes a symptom of one or more medical conditions, including bacterial vaginosis, trichomoniasis, yeast infection, gonorrhea and chlamydia, pelvic inflammatory disease, and human papillomavirus (HPV) or cervical cancer. In certain cases it is difficult to diagnose and to treat abnormal malodorous vaginal discharge having an atypical high pH. In general, vaginal pathology is curable by several cycles of anti-bacterial and anti-fungal medications. An additional approach consists on introducing an acidic flora to lower the local pH.
Severe mucous membrane malodor may occur even without a microorganism infection, and some are related to metabolic deficiencies and genetic disposition, such as in the case of trimethylaminuria. Currently there is no cure or approved drug to treat trimethylaminuria, but symptoms can be improved by making certain lifestyle changes, refreshing agents, common vitamins, watery douches, dietary restrictions, antibiotics, laxatives, activated charcoal, copper chlorophyllin, Apple cider vinegar, soaked tampons, probiotic pills, alum stick, cranberries, femunol preparation, enzara preparation, and the likes. The refreshing procedures were followed by powdered-perfuming techniques with balsamic fragrances, believing to mask or camouflage the bad vaginal smells.
Nonetheless, most mucous membrane malodor arise from one form or another of chemical degradation of amino acids, proteins and other nitrogen-rich and sulfur-rich naturally occurring substances. The main family of these compounds is the primary amines and the polyamines family, and the second major family is that of the sulfides. The malodor generated by both these families can potentially be neutralized by chemical agents. One exemplary source of the offensive smells of the vaginal-genital regions, resulting from proteins breakdown, is trimethylamine (TMA), which is the cause of the so-called fishy smell syndrome. TMA may accumulate in individuals that have a metabolic deficiency of an enzyme that oxidizes TMA to an odorless molecule easily soluble and drained out through the kidney.
Formulations for treating malodors associated with amine compounds have been suggested in the literature, and include harnessing the tendency of aldehydes to react with amines in what is known as Schiff base forming reaction, wherein an amine and an aldehyde interact to form an imine, to neutralize the amines, thereby mitigating the malodor problem. Exemplary background art for such approach include U.S. Pat. Nos. 9,055,849, 8,992,889, 8,674,167, 8,461,089 and 8,357,359, and U.S. Patent Application Publication Nos. 2014/0186285, 2013/0247941, 2013/0136712, 2013/0121950, 2011/0305659, 2011/0268667, 2011/0152804, 2011/0152157, 2011/0150817, 2011/0150816, 2011/0150815 and 2011/0150814. Additional background art include U.S. Pat. Nos. 5,733,535, 5,861,146, 5,939,060 and 8,835,511, U.S. Patent Application Publication Nos. 2012/0226248, 2013/0158491, 2013/0266642, 2014/0377207, 2014/0378920 and 2015/0093351, WO 2007113778, and EP1886698, EP2251016 and EP2263703.
Hyaluronic acid or its salt (HA) is an anionic, non-sulfated glycosaminoglycan that is naturally occurring in the body. It has been used extensively in many cosmetic and therapeutic applications as a filler and lubricant. Hyaluronic acid would be considered ideal as a carrier for compositions aimed for use in bodily sites that are prone to malodor, particularly vaginal mucus membranes that would benefit from its low pH. However, its use on mucus membrane is rather limited due to its low stability under physiological conditions caused mainly by enzymatic degradation, e.g., by hyaluronidase.
Attempts of overcoming the limitations associated with HA application, due to its rapid enzymatic degradation, typically involve introducing synthetic cross-linkers, for providing HA composite with reduced biodegradation rate, using high MW HA preparations, and employing specific or non-specific inhibitors of hyaluronidase. Hyaluronic acid degrading enzymes and inhibitors of the same have been described in the literature [see, for example, Sunitha, K. et al., Int J Biol Macromol., 2013, 55, pp. 39-46].
One of the inhibitors of hyaluronidase is N-acetylcysteine (NAC). NAC is a long-time used mucolytic medication, and is also known as exhibiting an anti-oxidative activity, as an antidote for acetaminophen overdose and as a chelating agent in systemic use. The use of systemic NAC, or NAC derivatives, alone or in combination with other antioxidants has been disclosed, for example, in WO 2010/086736, WO 2001/056572A1, WO 2006/116353A2, WO 2006/116353A3, WO 2011/044230A2, U.S. Pat. Nos. 6,420,429, 6,369,106 and 5,962,421, and U.S. Patent Applications having Publications Nos. 2011/0288134 and 2011/0244045. Topical application of NAC has been proposed as a method for prevention of sunburn in EP219455, for regulation of existing skin wrinkles and atrophy in U.S. Pat. No. 5,296,500, and for inhibition/prevention of photoaging-stain spots, when combined with a sun-blocking agent, to undamaged skin.
U.S. Patent Application Publication No. 2010/0004198 teaches polysaccharide (e.g., HA) formulations having increased longevity, which comprise the polysaccharide and an inhibitor of its degradation. The inhibitor can be a GAG, an antioxidant, a flavonoid, and the like.
U.S. Patent Application Publication No. 2003/0162732 teaches chemical complexes of cysteine or derivatives of cysteine and an amino sugar, as well as pharmaceutical compositions and dietary supplements comprising such complexes.
U.S. Pat. No. 5,804,594 teaches orally administered compositions comprising a sugar compound that is converted to a glycosaminoglycan in vivo, such as HA, an antioxidant, at least one amino acid and a transition metal, and their use in treating skin conditions.
Cosmetic and/or filler compositions comprising HA and optionally NAC, typically as an anti-oxidant, are also disclosed in U.S. Patent Application Publication Nos. 2009/0017091, 2005/0266064 and 2009/0143348, WO 2009/005790 and WO 2008/070893.
Additional background art includes WO 2006/135479, WO 2009/011849, WO 2006/121521, and WO 2006/121518, U.S. Pat. Nos. 5,707,635, 6,497,887, 7,321,000 and 8,784,893, U.S. Patent Application Publication Nos. 2004/0248847, 2005/0266064, 2011/0033540, 2013/0309217, 2014/0212388 and 2015/0190412 and WO 2003/011249.